Pharmaceutical compositions for parenteral administration

ABSTRACT

The invention comprises various aqueous PEG-carbohydrate-lipid based formulations of pharmaceutical active ingredients including compositions for intravenous injections. This invention relates to methods and compositions for improving solubility and the safety profile of pharmaceutical compounds. More particularly, the present invention relates to employing PEG-carbohydrate-lipid conjugates for formulating drug compositions having increased solubility or dispersivity and enhanced stability.

CROSS-REFERENCE TO A RELATED APPLICATION

The subject application claims priority to U.S. application Ser. No.13/532,023, filed on Jun. 25, 2012 which claims priority to U.S.provisional application Ser. No. 61/502,065, filed on Jun. 28, 2011,which the entire contents of both are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to methods and compositions for improvingsolubility and the safety profile of pharmaceutical compounds. Moreparticularly, the present invention relates to employingPolymer-carbohydrate-lipid conjugates, such as PEG-carbohydrate-lipidconjugates, for formulating drug compositions having increasedsolubility or dispersivity and enhanced stability.

BACKGROUND OF THE INVENTION

Delivery of hydrophobic drug compounds to the site of action is anongoing challenge in clinical research. It has been reported that 60-90%of new chemical entities in clinical and development are water insolubleor poorly soluble [A. M. Thayer (2010), Chemical & Engineering News,88(22): 13-18; C. A. Lipinski, J Pharmacol Toxicol Method 44 (2000)235-2490 and N. Gursoy and S. Benita, Biomed. Pharmacother. 58 (2004)173-182]. For example, Propofol is insoluble in water and is onlyslightly soluble in solutions having solubilizers commonly used inpreparing parenteral formulations such as propylene glycol, glycerin andPEG 400. Cyclodextrins, drug-lipid complexes, liposomes, and othersolubilizing agents such as Cremophor® and various PEG-lipid conjugateshave been tested as the delivery vehicles for Propofol. However, littleor substantially no significantly improvement in solubility andstability profiles may be achieved in these vehicles. What is needed arenew compositions and methods for formulating poor water soluble drugs invarious parenteral dosage forms.

SUMMARY OF THE INVENTION

In at least one aspect of the present disclosure, a pharmaceuticalcomposition for parenteral administration of a pharmaceutical activeingredient is provided. The composition comprises: a) an aqueoussolution or mixture; b) a pharmaceutical active ingredient; and c) asolubility enhancer comprising a Polymer-carbohydrate-lipid representedby at least one of chemical structures a) and b), wherein a) and b) are:

wherein: X₁, X₂, X₃ and X_(i) are the same or different linking groups;B is a central backbone; L is a lipid; S is carbohydrate; P is PEG; andD is lipid, carbohydrate or polymer.

In at least one other aspect of the present disclosure, a pharmaceuticalcomposition for parenteral administration of a pharmaceutical activeingredient is provided. The composition comprises: i) an aqueoussolution or mixture; ii) a solubility enhancer comprising at least onePolymer-carbohydrate-lipid; and iii) a pharmaceutical active ingredient.

In at least one aspect of the present disclosure, a process for making apharmaceutical composition for parenteral administration of apharmaceutical active ingredient is provided. The process comprises thesteps of: adding an aqueous solution of PEG-carbohydrate-lipids to avessel; adding a pharmaceutical active ingredient in liquid or Slurryform to the vessel; mixing until the pharmaceutical active ingredient isvisually dispersed in the aqueous solution of PEG-carbohydrate-lipids;adding pre-dissolved excipients to the vessel; and mixing until ahomogenous solution is achieved.

BRIEF DESCRIPTION OF THE INVENTION

The invention comprises various aqueous and PEG-carbohydrate-lipid basedformulations of poorly water soluble drugs including compositions forparenteral preparations such as intravenous injection. In one aspect theinvention comprises a solution of lipophilic compound andPEG-carbohydrate-lipid (s) to enhance the solubility or dispersivity oflipophilic compounds in aqueous solutions.

In at least one aspect of the present disclosure, a pharmaceuticalcomposition for parenteral administration of a pharmaceutical activeingredient is provided. The composition comprises: an aqueous solutionor mixture; a solubility enhancer comprising at least onepolymer-carbohydrate-lipid; and a pharmaceutical active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and constitute apart of this specification, illustrate one or more embodiments of thepresent invention and, together with the detailed description, serve toexplain the principles and implementations of the invention.

In the drawings:

FIG. 1 shows a representation of the chemical structures ofLipid-carbohydrate-PEG conjugates;

FIG. 2 shows mouse pharmacokinetic profiles of propofol formulationsafter IV dosing; and

FIG. 3 schematically shows a manufacturing flow chart for PropofolSolution for Injection.

DETAILED DESCRIPTION

Embodiments of the present invention are described herein in the contextof lipid-carbohydrate-polymer conjugates for increasing the solubilityand enhancing the delivery of lipophilic drug molecules. Those ofordinary skill in the art will realize that the following detaileddescription of the present invention is illustrative only and is notintended to be in any way limiting. Other embodiments of the presentinvention will readily suggest themselves to such skilled persons havingthe benefit of this disclosure. Reference will now be made in detail toimplementations of the present invention as illustrated in theaccompanying drawings.

In the interest of clarity, not all of the routine features of theimplementations described herein are shown and described. It will, ofcourse, be appreciated that in the development of any such actualimplementation, numerous implementation-specific decisions may need bemade in order to achieve specific goals, such as compliance withapplication and business related constraints, and that these specificgoals may vary from one implementation to another and from one developerto another. However, development and implementation of the disclosed maybe a routine undertaking of engineering for those of ordinary skill inthe art having the benefit of this disclosure.

U.S. patent application Ser. Nos. 13/364,967 and 13/354,726, which arehereby incorporated by reference, may teach the formation of spontaneousliposomes by employing certain lipid-carbohydrate-polyethleneglycol(LCP) conjugates. They may describe how to prepare thePEG-carbohydrate-lipid conjugates and its applications by simply addingthe conjugate to an aqueous solution. It has been demonstrated that LCPsmay be useful for solubilizing hydrophobic drugs without the formationof liposomes or microemulsions.

Over last three decades, some of promising drug carriers that have beeninvestigated in systemic delivery systems includes liposomes, polymericnanoparticles, polymeric micelles, ceramic nanoparticles and dendrimers(Cherian et al. Drug. Dev. Ind. Pharm, 26: (2000) 459-463; Lian and Ho.J. Pharm. Sci, 90 (2001) 667-680; Adams et al. Pharm. Sci, 92 (2003)1343-1355; Na et al. Eur. J. Med. Chem, 41 (2006) 670-674; Kaur et al.J. Control. Rel, 127(2008) 97-109). Systemic drug delivery may beachieved by intravenous or intraperipheral injection and therefore isnon-invasive. The drugs may be administered repeatedly as needed.However, in order to achieve therapeutic concentrations at the targetsite, systemic administration may require large dosages with relativelyhigh vehicle contents which may cause side effects such as allergicreactions [“Cremophor-based paclitaxel ‘chemo’ drug triggers fatalallergic reactions,” The Medical News. 9 Jun. 2009].

Polyethylenglycol (PEG) is widely used as a water soluble carrier forpolymer-drug conjugates. PEG may undoubtedly be the most studied andapplied synthetic polymer in the biomedical field [Duncan, R. NatureRev. Drug Discov. 2003, 2, 347-360]. As an uncharged, water-soluble,nontoxic, nonimmunogenic polymer, PEG may be an ideal material forbiomedical applications. Covalent attachment of PEG to biologicallyactive compounds is often useful as a technique for alteration andcontrol of biodistribution and pharmacokinetics, minimizing toxicity ofthese compounds [Duncan, R. and Kopecek, J., Adv. Polym. Sci. 57 (1984),53-101]. PEG possesses several beneficial properties: very low toxicity[Pang, S. N. J., J. Am. Coil. Toxicol, 12 (1993), 429-456], excellentsolubility in aqueous solutions [Powell, G. M., Handbook of WaterSoluble Gums and Resins, R. L. Davidson (Ed.), Ch. 18 (1980),MGraw-Hill, New York], and extremely low immunogenicity and antigenicity[Dreborg, S, Crit. Rev. Ther. Drug Carrier Syst., 6 (1990), 315-365].The polymer is known to be non-biodegradable, yet it is readilyexcretable after administration into living organisms. In vitro studyshowed that its presence in aqueous solutions has shown no deleteriouseffect on protein conformation or activities of enzymes. PEG alsoexhibits excellent pharmacokinetic and biodistribution behavior.[Yamaoka, T., Tabata, Y. and Ikada, Y., J. Pharm. Sci. 83 (1994),601-606].

When used as a delivery vehicle, polymer-lipid conjugates may have thecapacity to improve the pharmacology profile and solubility oflipophilic drugs. The novel polymer-carbohydrate-lipid conjugatesdisclosed in the earlier inventions may also provide other potentialadvantages over conventional polymer-lipids, i.e., PEG-lipids, such asminimizing side effects and toxicities associated with therapeutictreatments.

The important role of sugars in many specific interactions in livingsystems is well recognized. Large molecular weight carriers such asproteins or liposomes may be modified with sugars for specific drugdelivery (Monsigny M, Roche A C, Midoux P and Mayer R., Adv DrugDelivery Rev., 14 (1994):1-24; Palomino E. Adv Drug Delivery Rev., 13(1994)311-323]. Lipid-sugar particles have been used for drug deliveryto the brain for providing prolonged duration local anesthesia wheninjected at the sciatic nerve in rats [Kohane D S, Lipp M, Kinney R.,Lotan N, Langer R., Pharm. Res. 17 (2000) 1243-1249]. Since sugar-lipidsare composed of materials that occur naturally in the human bodysuggests potential advantages over some other polymer-basedcontrolled-release terms of biocompatibility [Kohane D S, Lipp M, KinneyR, Anthony D, Lotan N, Langer R., J. Biomed. Mat. Res. 59 (2002)450-459; Menei P, Daniel V, Montero-Menei C, Brouillard M,Pouplard-Barthelaix A, Benoit J P., Biomaterials, 14 (1993) 470-478].Lipid-sugars may have a good biocompatibility as shown by the results ofthe in vitro and in vivo studies [Kohane D S, Lipp M, Kinney R, AnthonyD, Lotan N, Langer R., J. Biomed. Mat. Res. 59 (2002) 450-459].

A preferred embodiment of the present disclosure may comprise anaqueous-based, injectable drug solution including and not limited tooleoyltri-ethylenetetramine-polyethyleneglycol lactobionate (OTL-PEG) oroleoyldiethylenetetramine-dodecaethylene glycol lactobionate (ODL-PEG).In at least one aspect of the present disclosure, the solution includesa drug molecule in concentrations ranging from 0.05 mg/mL to 50 mg/mLand the ratio of PEG-lipid to the drug ranges from 0.2 to 25. In atleast one other aspect of the present disclosure, the concentration ofdrug molecule ranges from 0.5 mg/mL to 50 mg/mL. In at least oneadditional aspect of the present disclosure, the concentration of drugmolecule ranges from 0.5 mg/mL to 10 mg/mL and the percent ofPEG-carbohydrate-lipid ranges from 0.5 to 10 (w/v) of the totalsolution.

Further aspects of the present disclosure may provide aqueous,injectable drug solutions in which the diluent consists of 0.5 to 25percent (w/v) of the PEG-carbohydrate-lipid and 75 to 99.5 percent (v/v)of water or a buffer or saline or dextrose solution. Also preferable areaqueous, injectable drug solutions of this invention in which 85 to 99percent (v/v) of the total solution is water or a buffer or saline ordextrose solution.

In at least one aspect of the present disclosure, aqueous injectabledrug solutions according to the present invention comprise lipophilicdrug compound in LCP lipids including and not limited to OTL-PEG orODL-PEG plus aqueous media at concentrations of a drug ranging from 0.5mg/mL to 50 mg/mL, 0.5 to 25 percent (w/v) of PEG-carbohydrate lipid,and 75 to 99.5 percent (v/v) water, wherein the concentration of drug inthe combined solution ranges from 0.5% to 5%.

The aqueous injectable drug solutions of the present disclosure may beadministrated by bolus injection or by infusion. Infusion may bepreferable for such solutions where the concentration of drug in isgreater than 0.01 mg/mL. In case of an infusion, the length of aninfusion may be preferable 30 minutes to 6 hours and may not be morethan 24 hours.

Aspects of the present disclosure involve solubilizing a drug or drugs,by using one or more amphipathic PEG conjugates. A combination of LCPsand polysorbates may be preferred solubilizing agents, in which acylchains comprise the lipophilic portion of the conjugate. Examples ofLCPs are shown in FIG. 1.

A branched PEG-carbohydrate-lipid may also be an excellent solubilizingagent, in which the polymer comprises the more than single PEG chains ofthe conjugate. Similarly, branched-PEG-carbohydrate-lipids may also beused as solubilizing agents. As with LCP solubilizing agents, thesecompounds typically are waxy solid or semisolids at the temperature ofsolubilization, these PEG-carbohydrate-lipids typically have meltingpoints above about 25 degrees Centigrade. Such solubilizing agents mayalso be used to prepare IV formulations and oral or topical liquids.

A first step for solubilization may comprise combining the drugcompound(s), with an amphipathic PEG conjugate(s) which may be semisolidor solid at the temperature of solubilization. For formulating a drugsolution at room temperature (which may be preferred), a concentratedsolution of a conjugate may be desired. Such solubilization may be doneby first adding the liquid form of a drug to the concentrated solutionof the conjugates. The aqueous solution may be further diluted withwater or a buffer. Alternatively, the drug compound(s) may bepre-dissolved in a small amount of acid, base or alcohol, then mix withthe PEG-carbohydrate-lipids in aqueous solution.

By performing solubilization at elevated temperatures, conjugates withhigher melting temperatures may be used as solubilizing agents. Whenforming aqueous solutions, the aqueous solution may also be preferablyadded at an elevated temperature.

The LCP lipids shown in Table 1 may be suitable for use in variousaspects of the present disclosure. LCPs with oxy or amide or succinyllinkers (X=oxygen or carbonyl or succinyl) may be preferred, though LCPswith other linkers may be used.

The lipid-carbohydrate polymer conjugates shown in FIG. 1 may besuitable for use in various aspects of the present disclosure. Where X₁,X₂, X₃ and X_(i) are the same or different linking groups; “B” is acentral backbone; “L” is a lipid; “S” is carbohydrate; “P” is a polymer;and “D” is lipid (the same or different than “L”) or carbohydrate (thesame or different than “5”) or polymer (the same or different than “P”).

Backbone (B) may comprise glycerol or glycerol-like analogues or linearamines (tri- or tetra-amines) or amino acids having three availablebinding sites; where the lipid (L) may comprise carboxylic acidsincluding and not limited to diacylglycerol or fatty acids or bileacids; sugar (C) may comprise a carbohydrate including monosaccharidesor disaccharides or oligosaccharides; X₁, X₂ and X₃ and X_(i) are thesame or different linkers and X represents an oxy or single or replicatelinkers or combination of two or more molecules in between the backboneand one of functional groups. The General Structure is meant to includeall racemers or structural isomers of the structure, as they may befunctionally equivalent. The PEG chain (P) may be a single PEG or abranched PEG chains consisting of 5 to 45 subunits. There may be aterminal group (R) on the PEG chain which may comprise a wide variety ofchemical moieties. In at least one aspect of the present disclosure, Rhas a molecular weight of less than about 650. D may comprise asecondary sugar or lipid or PEG. The Lipid-carbohydrate-PEG conjugatesmay be useful for applications other than liposomes, e.g., as a solvent.

If a terminal group is attached to the PEG chain in FIG. 1, it maycomprise a wide variety of chemical moieties. Such moieties may have amolecular weight of less than 650. Such moieties include —NH₂, —COOH,—OCH₂CH₃, —OCH₂CH₂OH, —COCH═CH₂, —OCH₂CH₂NH₂, —OSO₂CH₃, —OCH₂C₆H₆,—OCH₂COCH₂CH₂COONC₄H₄O₂, —CH₂CH₂═CH₂, C₁₀H₁₆N₂O₃S and —OC₆H₆. Theterminal group may be a functional group that facilitates linking oftherapeutic or targeting agents to the surface of lipid vesicleaggregates. Amino acids, amino alkyl esters, biotins, maleimide,diglycidyl ether, maleinimido propionate, methylcarbamate,tosylhydrazone salts, azide, propargyl-amine, propargyl alcohol, NHSesters (e.g., propargyl NHS ester, NHS-biotin, sulfo-NHS-LC-biotin, orNHS carbonate), hydrazide, succinimidyl ester, succinimidyl tartrate,succinimidyl succinate, and toluenesulfonate salt may be useful for suchlinking. Linked therapeutic and targeting agents may include Fabfragments (fragment antigen-binding), cell surface binding agents, andthe like. Additionally, the terminal group may include functionalcell-targeting ligands such as folate, transferrin and molecules such asmonoclonal antibodies, ligands for cellular receptors or specificpeptide sequences may be attached to the liposomal surface to providespecific binding sites. The terminal group may be neutral or includeeither negatively or positively charged head-groups such asdecanolamine, octadecylolamine, octanolamine, butanolamine,dodecanolamine, hexanolamine, tetradecanolamine, hexadecanolamine,oleylamine, decanoltrimethylaminium, octadecyloltrimethylaminium,octanoltrimethyl-aminium, butanoltrimethylaminium,dodecanoltrimethylaminium, hexanoltrimethylaminium,tetradecanoltrimethylaminium, hexadecanoltrimethylaminium,oleyltrimethylaminium, for example. Other useful R groups include alkylgroups such as alkoxy moieties, amino acids, and sugars includingmonosaccharides, disaccharides, trisaccharides and theoligosaccharides—containing 1, 2, 3, and 4 or more monosaccharide unitsrespectively. Additionally, targeting moieties such as antibodyfragments and vitamins may also be used as R groups. Generally, the Rgroup may be highly soluble in water. The molecular weight of the Rgroup may be less than about 650, and for most applications the R groupmay be easily polarized, in order to increase the binding andinteraction with proteins at the targeted sites.

TABLE 1 PEG-lipid (Lipid-carbohydrate-polyethyleneglycols) Shorthandname Name MAGC-PEGs monoacylglycerol-carbohydrate-polyethylene glycolsMAPC-PEGs monoacylpolyamine-carbohydrate-polyethylene glycols MAAC-PEGsmonoacylamino acid-carbohydrate-polyethylene glycol ODL-TrpPEGsoleoyldiethylenetriamine-tryptophanyl PEG LOS-PEGsN-lactobionyloleoyl-mPEG serinate LOS-bioPEGsN-lactobionyloleoyl-biotinylated PEG serinate OAPDL-11oleoyl-N-(3-aminopropyl)propane-1,3-diamine- Undecaethylene glycolmethyl ether Lactobionate GDODL-12:dioleoylglyceroldiethylenetriamine-monomethoxyl dodecaethylene glycolether lactobionate GMODL-12 dimyristoylglyceroldiethylenetriamine-monomethoxyl dodecaethylene glycol ether lactobionateGML-12 myristoylglycerol-dodecaethylene glycol lactobionate GOL-12oleoylglycerol-dodecaethylene glycol lactobionate MDTL-12myristoyldiethylenetetramine-dodecaethylene glycol lactobionate ODL-12oleoyldiethylenetriamine-dodecaethylene glycol lactobionate ODL-15oleoyldiethylenetriamine-pentadecaethylene glycol lactobionate ODTL-12oleoyldiethylenetetramine-dodecaethylene glycol lactobionate ODTL-15oleoyldiethylenetetramine-pentadecaethylene glycol lactobionate MTL-12myristoyltriethylenetetramine-dodecaethylene glycol lactobionate OTL-12oleoyltriethylenetetramine-dodecaethylene glycol lactobionate OTL-15oleoyltriethylenetetramine-pentadecaethylene glycol lactobionateGDODL-12 dioleoylglycerol-diethylenetriamine-monomethoxyl polyethyleneglycol ether lactobionate OAPEL-PEGoleoyl(aminopropylamino)ethanoyl-mPEG Lactobionate LOS-bioPEGN-lactobionyloleoyl-biotinylated PEG Serinate LOL-bioPEGN-lactobionyloleoyl-biotinylated PEG Lycinate DCAL-PEGN-desoxycholylaspartate-mPEG lactobionate OAL-mPEGoleoylaminopropanediol-mPEG lactobionate OAL-bioPEGoleoylaminopropanediol-biotinylated PEG lactobionate ODL-ThrPEGoleoyldiethylenetriamine-threoninyl PEG lactobionate ODL-bioPEGoleoyldiethylenetriamine-biotinylated PEG lactobionate ODL-PEGoleoyldiethylenetriamine-PEG lactobionate

Mixtures of PEG-carbohydrate-lipids may be used in the presentdisclosure in the place where combinations of PEG-carbohydrate-lipidsare used, the properties of the lipid mixture (e.g., melting point oraverage size of the PEG chain) may be calculated by known methods ordetermined empirically.

The manufacture of parenteral solution may comprise first adding a drugto a concentrated PEG-carbohydrate-lipid solution and mixing untilhomogenous, which may be accomplished at room temperatures. Next,premixed aqueous integrants may be added to the lipid-drug mixture andmixed until a homogenous solution is obtained. The solution may then befiltered for sterility while maintaining an overlay of sterile-filterednitrogen during the process. Appropriate volumes of the solution may befilled into ampules and sealed using aseptic technique. Sterileconditions may be maintained throughout the filtering, filling, andsealing operations in accordance with standard manufacturing proceduresfor injectables. While the formulated product may be stable at roomtemperature, it may be preferably stored under refrigeration forextended shelf life.

A preservative may be desired when the sterile-filtered process isprevented by high concentrations of PEG-carbohydrate-lipids, thepossible preservatives may be selected from a group of antimicrobialagents consisting of benzyl alcohol, chlorobutanol, methylparaben,propylparaben, phenol, ethylenediaminetetraacetic acid, and m-cresol.

In one aspect of the present disclosure, a pharmaceutical compositionfor administration by intravenous injection is provided. The compositioncomprises an aqueous solution; a PEG-carbohydrate-lipid or combinationof PEG-carbohydrate-lipids; and a drug at a concentration between about0.05 mg/mL and about 50 mg/mL. The weight ratio of thePEG-carbohydrate-lipids to the drug may be between about 0.2 and 25. Theaverage MW of PEG chains in the PEG-carbohydrate-lipid or mixture ofPEG-carbohydrate-lipids may be less than about 1500. The concentrationof a drug may preferably be between about 0.2 mg/ml to 50 mg/ml. Theconcentration of PEG-carbohydrate-lipids (s) may preferably be betweenabout 0.5 to 25 percent (w/v) of the total solution.

In another aspect, the disclosure provides a method of making apharmaceutical composition suitable for administration by intravenousinjection. The method comprises mixing a PEG-carbohydrate-lipid orcombination of PEG-carbohydrate-lipids with a drug and adding an aqueoussolution while mixing to create a suspension. The final concentration ofthe drug may preferably be between about 0.05 mg/ml and about 50 mg/ml.The weight ratio of the total PEG-lipid to the drug compound maypreferably be between about 0.2 and 25. The average MW of PEG chains inthe PEG-carbohydrate-lipids or combination of PEG-carbohydrate-lipidsmay preferably be less than about 1500. The method may further comprisesealing the aqueous suspension in a sterile container or addingantimicrobial preservatives.

In another aspect of the present disclosure, a method of treating adisease in a mammal is provided. The method comprises preparing acomposition comprising an aqueous solution, a PEG-carbohydrate-lipid orcombination of PEG-carbohydrate-lipids, and drug compound at aconcentration between about 0.05 mg/mL and about 50 mg/mL. The weightratio of the PEG-carbohydrate-lipids to the drug may be between about0.2 and 25. The composition may be administered to the mammalintravenously. The average MW of single PEG chains in thePEG-carbohydrate-lipid or combination of PEG-carbohydrate-lipids ispreferably less than about 1500. The concentration of drug may bebetween about 0.2 mg/mL to 25 mg/mL. The concentration ofPEG-carbohydrate-lipids may be between about 0.5 to 25 percent (w/v) ofthe total solution. The composition may further comprise antimicrobialpreservatives, where the concentration of antimicrobial preservativesmay be between about 0.1 to 2%. The disease being treated may be acancer or a fungal infection, for example. The method may also be usedto provide for general anesthesia for surgical procedures or wherehypnotic agents are desired.

The following examples intend to further illustrate the practice of thepresent invention.

Example 1 Preparation of Propofol Solution for Injection

A propofol solution suitable for intravenous delivery was prepared asdescribed in FIG. 3, showing Scheme 1. Scheme 1, FIG. 3, shows amanufacturing flow chart for Propofol Solution for Injection.

An aqueous solution of PEG-carbohydrate-lipids was added to a vesselequipped with a mixer propeller. The drug substance was added withconstant mixing. Mixing was continued until the drug is visuallydispersed. Pre-dissolved excipients in water were slowly added to thevessel with adequate mixing. Mixing continued until a homogenoussolution was achieved. Sterile conditions should be maintainedthroughout the process for producing clinical supplies. A sampleformulation is described in Table 2.

TABLE 2 Ingredient mg/mL Propofol 10.0 PEG-carbohydrate-lipid 30Glucose¹ 50 Purified Water qs 1 mL ¹optional

PEG-carbohydrate-lipid may be selected from Table 1, where n=8 or higher(i.e., the molecular weight of the PEG chain is greater than about 350)or lipid-carbohydrate-PEG, where PEG chain contains 8 to 16 subunits.The targeted pH is in a range of 4.0 to 7.5. Diluted NaOH (i.e., 10N) orHCl solution (i.e., 6N) may be used to adjust pH if necessary.

Example 2 Preparation of Propofol Solution for Injection

A propofol solution suitable for intravenous delivery of propofol wasprepared the same as in Example 1. A concentrated PEG-carbohydrate-lipidwas charged to a vessel equipped with a mixer propeller. The drugsubstance was added with constant mixing. Mixing continued until thedrug was visually dispersed in the lipid solution. Pre-dissolvedexcipients in water were slowly added to the vessel with adequatemixing. Sterile conditions should be maintained throughout the processfor producing clinical supplies. Mixing continued until fully ahomogenous solution was achieved. A sample formulation is described inTable 3.

TABLE 3 Ingredient mg/mL Propofol 10.0 PEG-carbohydrate-lipid 30.0Sodium Chloride 9.0 Sodium Hydroxide See below Hydrochloric Acid Seebelow Purified Water qs 1 mL

The lipid-carbohydrate-PEG may be selected from Table 1, where PEG chaincontains between 8 to 16 subunits. Sodium hydroxide was used to preparea 10% w/w solution in purified water. The targeted pH was in a range of4.0 to 7.5. The NaOH solution or HCl (6N) was used to adjust pH asnecessary.

Example 3 Preparation of Propofol Solution or Suspension for Injection

A propofol solution suitable for intravenous delivery of propofol wasprepared the same as in Example 1. A concentrated solution ofPEG-carbohydrate-lipid was charged to a vessel equipped with a mixerpropeller. The drug substance was added with constant mixing. Mixingcontinued until the drug was visually dispersed in the lipid.Pre-dissolved excipients in water were slowly added to the vessel withadequate mixing. Mixing continued until fully a homogenous solution wasachieved. Sterile conditions should be maintained throughout the processfor producing clinical supplies. A sample formulation is described inTable 4.

TABLE 4 Ingredient mg/mL Propofol 10.0 PEG-carbohydrate-lipid 15.0Sodium Chloride 9.0 Sodium Hydroxide See below Hydrochloric Acid Seebelow Sodium Benzoate 20.0¹ Purified Water qs 1 mL ¹preservative is notneeded if sterile-filtered is used.

The PEG-carbohydrate-lipid may be selected from Table 1, where PEG chaincontains 8 to 16 subunits. Sodium hydroxide was used to prepare a 10%w/w solution in purified water. The targeted pH was in a range of 4.0 to7.5. The NaOH solution or HCl (6N) was used to adjust pH as necessary.

Example 4 Cisplatin IV Injectable Solution

The IV solution is prepared as in Example 1. A sample formulation isdescribed in Table 5.

TABLE 5 Ingredient mg/mL Cisplatin 20.0 PEG-carbohydrate-lipid 20.0Sodium Chloride 9.0 Sodium Hydroxide See below Hydrochloric Acid Seebelow Purified Water qs 1 mL

The PEG-carbohydrate-lipid may be selected from Table 1, where PEG chaincontains between 8 to 16 subunits. Sodium hydroxide was used to preparea 10% w/w solution in purified water. The targeted pH was in a range of4.0 to 7.5. The NaOH or HCl (6N) solution was used to adjust pH asnecessary.

Example 5 Docetaxel IV Injectable Solution

The drug substance was charged into a vessel equipped with a mixerpropeller. Dehydrated alcohol was added with constant mixing. Mixingcontinued until the drug was visually disappeared in the Alcohol.Pre-dissolved lipid and excipients in water were slowly added to thevessel with adequate mixing. Mixing continued until fully a homogenoussolution was achieved. Sterile conditions should be maintainedthroughout the process for producing clinical supplies. A sampleformulation is described in Table 6.

TABLE 6 Ingredient mg/mL Docetaxel 10.0 PEG-carbohydrate-lipid 25Dehydrated Alcohol 10.0 Sodium Chloride 9.0 Sodium Hydroxide See belowHydrochloric Acid See below Purified Water qs 1 mL

The PEG-carbohydrate-lipid may be selected from Table 1, where PEG chaincontains 8 to 16 subunits. Sodium hydroxide was used to prepare a 10%w/w solution in purified water. The targeted pH was in a range of 4.0 to7.5. The NaOH or HCl (6N) solution was used to adjust pH as necessary.

Example 6 Paclitaxel IV Injectable Solution

The IV solution was prepared as in Example 5, except that the dehydratedalcohol contained 5% of sodium hydroxide (v/v). A sample formulation isdescribed in Table 7.

TABLE 7 Ingredient mg/mL Paclitaxel 12.0 PEG-carbohydrate-lipid 30.0Dehydrated Alcohol 10.0 Sodium Chloride 9.0 Sodium Hydroxide See belowHydrochloric Acid See below Purified Water qs 1 mL

The PEG-carbohydrate-lipid may be selected from Table 1, where PEG chaincontains 8 to 16 subunits. Sodium hydroxide was used to prepare a 10%w/w solution in purified water. The targeted pH was in a range of 4.0 to7.5. The NaOH or HCl (6N) solution was used to adjust pH as necessary.

Example 7 Triazole Fungicide IV Injectable Solution or Suspension

The IV solution was prepared as in Example 5. A sample formulation isdescribed in Table 8.

TABLE 8 Ingredient mg/mL Active 10.0 PEG-carbohydrate-lipid 30.0Dehydrated alcohol 20.0 Sodium Hydroxide See below Hydrochloric Acid Seebelow Sodium Benzoate 20.0 Purified Water qs 1 mL

The active is voriconazole or posaconazole. PEG-carbohydrate-lipid maybe selected from Table 1, where PEG chain contains 8 to 16 subunits.Sodium hydroxide was used to prepare a 10% w/w solution in purifiedwater. The targeted pH was in a range of 4.0 to 7.5. The NaOH or HCl(6N) solution was used to adjust pH as necessary.

Example 8 Pharmacokinetic Profile of Propofol Formulations

Groups of three male mice (B6D2F1, 4 weeks old and weights of 20 to 28grams were used for the studies. Pharmacokinetics (PK) were performed onheparinized mouse plasma samples obtained typically at after the bolusIV injection at 1, 3, 8, 12, 15, 20, 30, 45 and 60 minutes for Propofol.Samples were analyzed using a HPLC-MS method. To determine the level ofthe drug, the drug was first isolated from plasma with a samplepre-treatment. Acetonitrile were used to remove proteins in samples. Anisocratic HPLC-MS/MS method was then used to separate the drugs from anypotential interference. Drug levels were measured by MS detection with amultiple reaction monitoring (MRM) mode. PK data was analyzed using theWinNonlin program (ver. 5.3, Pharsight) compartmental models ofanalysis.

FIG. 2 shows mouse PK profiles of propofol formulations with (1) 1% ofPropofol in a formulation consisting of 2.5% of OAPDL-12 in salinesolution and (2) a commercial product of 1% Propofol The drug wasadministered intravenously and the dosing strength was 15 mg/kg. Fromthe 2-compartmental calculations, the AUC were 101.6 mg·hr/L with adistribution half-life of 0.68 minutes and elimination half-life of 6.03minutes for formulation (1) and 71.4 mg·hr/L with a distributionhalf-life of 0.69 minutes and elimination half-life of 9.3 minutes forthe formulation (2), respectively. From the non-compartmentalcalculations, the AUC were 184.2 mg·hr/L with a half-life of 49.45minutes for formulation (1) and 133.8 mg·hr/L with a half-life of 19.25minutes for formulation (2), respectively.

While preferred aspects and embodiments of the present invention havebeen described, those skilled in the art will recognize that other andfurther changes and modifications can be made without departing from thespirit of the invention, and all such changes and modifications shouldbe understood to fall within the scope of the invention.

What is claimed is:
 1. A pharmaceutical composition for parenteraladministration of a pharmaceutical active ingredient, the compositioncomprising: a) an aqueous solution or mixture; b) a pharmaceuticalactive ingredient; and c) a solubility enhancer comprising at least oneof oleoyl-diethylenetriamine-PEG-lactobionate,oleoyl-N-(3-aminopropyl)propane-1,3-diamine-undecaethylene-glycol-methyl-ether-lactobionate,oleoy-(aminopropylamino)ethanoyl-mPEG-lactobionate,myristoyl-diethylenetriamine-dodecaethylene-glycol-lactobionate,myristoyl-triethylenetetramine-dodecaethylene-glycol-lactobionate,oleoyl-triethylenetetramine-dodecaethylene-glycol-lactobionate, andoleoyl-triethylenetetramine-pentadecaethylene-glycol-lactobionate. 2.The pharmaceutical composition of claim 1 comprising the pharmaceuticalactive ingredient at a concentration between about 0.05 mg/mL and about50 mg/mL.
 3. The pharmaceutical composition of claim 1 comprising aweight ratio of the solubility enhancer to the pharmaceutical activeingredient between about 0.2 and about
 25. 4. The pharmaceuticalcomposition of claim 1 wherein the pharmaceutical active ingredient isselected from the group consisting of propofol, cisplatin, docetaxel,paclitaxel, posaconazole, voriconazole, and combinations thereof.
 5. Thepharmaceutical composition of claim 4 wherein the pharmaceutical activeingredient comprises propofol at a concentration in the pharmaceuticalcomposition of between about 0.2 mg/mL to about 25 mg/mL.
 6. Thepharmaceutical composition of claim 4 wherein the pharmaceutical activeingredient comprises cisplatin at a concentration in the pharmaceuticalcomposition of between about 0.2 mg/mL to about 50 mg/mL.
 7. Thepharmaceutical composition of claim 4 wherein the pharmaceutical activeingredient comprises docetaxel at a concentration in the pharmaceuticalcomposition of between about 0.2 mg/mL to about 25 mg/mL.
 8. Thepharmaceutical composition of claim 4 wherein the pharmaceutical activeingredient comprises paclitaxel at a concentration in the pharmaceuticalcomposition of between about 0.2 mg/mL to about 25 mg/mL.
 9. Thepharmaceutical composition of claim 4 wherein the pharmaceutical activeingredient comprises posaconazole at a concentration in thepharmaceutical composition of between about 0.5 mg/mL to about 40 mg/mL.10. The pharmaceutical composition of claim 4 wherein the pharmaceuticalactive ingredient comprises voriconazole at a concentration in thepharmaceutical composition of between about 0.5 mg/mL to about 40 mg/mL.11. The pharmaceutical composition of claim 1 wherein the solubilityenhancer comprises oleoyl-diethylenetriamine-PEG-lactobionate.
 12. Thepharmaceutical composition of claim 1 wherein the solubility enhancercomprisesoleoyl-N-(3-aminopropyl)propane-1,3-diamine-undecaethylene-glycol-methyl-ether-lactobionate.13. The pharmaceutical composition of claim 1 wherein the solubilityenhancer comprises oleoy-(aminopropylamino)ethanoyl-mPEG-lactobionate.14. The pharmaceutical composition of claim 1 wherein the solubilityenhancer comprisesmyristoyl-diethylenetriamine-dodecaethylene-glycol-lactobionate.
 15. Thepharmaceutical composition of claim 1 wherein the solubility enhancercomprisesmyristoyl-triethylenetetramine-dodecaethylene-glycol-lactobionate. 16.The pharmaceutical composition of claim 1 wherein the solubilityenhancer comprisesoleoyl-triethylenetetramine-dodecaethylene-glycol-lactobionate.
 17. Thepharmaceutical composition of claim 1 wherein the solubility enhancercomprisesoleoyl-triethylenetetramine-pentadecaethylene-glycol-lactobionate.